This application claims priority to U.S. provisional patent application Ser. No. 60/024,551 filed Aug. 26, 1996. The invention generally relates to the production of radionuclides for diagnostic and therapeutic use, and specifically, to the production of .sup.186 Re, .sup.188 Re and other radionuclides using an inorganic Szilard-Chalmers reaction.
For a number of years, isotopes of rhenium, particularly .sup.186 Re and .sup.188 Re, have been of interest to the nuclear medicine community for use in therapeutic applications. Both .sup.186 Re and .sup.188 Re are beta-emitting radionuclides with relatively short half lives of 90 hours and 17 hours, respectively. The maximum beta energy of .sup.186 Re is 1.07 MeV, while that of .sup.186 Re is 2.12 MeV. In addition, both isotopes exhibit gamma emissions (9.2%, 137 keV and 15%, 155 keV, respectively) suitable for evaluation of in vivo distribution of rhenium agents. Recent measurements of .sup.186 Re by the National Institute of Standards and Technology (Coursey et al., Appl. Radiat. Isot. Vol. 42, No. 9, 865, 1991) showed that the decay half-life of .sup.186 Re is 89.25.+-.0.07 hours and that the probability of emission of the principal gamma ray at 137keV was 0.0945.+-.0.0016. The beta emission at 1.077MeV is 71.4% abundant, the emission at 0.94 MeV contributes 21.3%, and 7.28% by electron capture.
Major areas of interest for .sup.186 Re and .sup.188 Re include: radiolabeled monoclonal antibodies (Su et al., J. Nucl. Med. Abstr. 484 31, 823, 1990; DiZio et al., Bioconjugate Chem 2, 353, 1991; Weiden et al., Radiopharm 5, 141, 1992); lung and colon carcinomas (Schroff et al., Immunoconjugates Radio-pharmaceuticals 3, 99, 1990); labeled progestin conjugates for possible treatment of steroid receptor-positive tumors (DiZio et al., J. Nucl. Med. Vol. 33, No. 4, 558, 1992); labeled phosphonate complexes (.sup.186 Re-HEDP) for relief of pain associated with metastatic bone cancer (Pipes et al., J. Nucl. Med. Abstr. 254, 31, 768, 1990); and labeled dimercaptosuccininic acid (.sup.186 Re-DMSA) for tumors of the head and neck (Bisunadan et al., Appl. Radiat. Isot. 42, 167, 1991). Recently, Ehrhardt et al. evaluated the formulation of .sup.186 Re labeled human serum albumin microspheres in an animal model as a potential radiation synovectomy agent Rhenium-186 labeled hydroxyapatite particles are also being evaluated as a potential radiopharmaceutical for radiation synovectomy (Chinol et al., J. Nucl. Med., 34: 1536, 1993; Clunie et al., Nucl. Med., 36: 51, 1995).
.sup.186 Re and .sup.188 Re can be produced via a (n,.gamma.) reaction from .sup.185 Re and .sup.187 Re target nuclides, respectively. According to one approach, a .sup.185 Re target nuclide--present either as a thick metal target of isotopically enriched elemental .sup.185 Re (95%) or as a water soluble perrhenate salt (e.g. aluminum perrhenate, Al(.sup.185 ReO.sub.4).sub.3)--is irradiated with thermal neutrons at a flux of about 10.sup.13 -10.sup.15 n/cm.sup.2 s to form a product .sup.186 Re nuclide. When a elemental rhenium target is employed, the product nuclide is recovered by oxidizing the rhenium metal with an oxidizing solvent such as H.sub.2 O.sub.2 or nitric acid to obtain a soluble perrhenate solution which includes the product nuclide. When a perrhenate salt target is employed, the product nuclide is recovered by dissolving the irradiated perrhenate target in water or saline solution (Ehrhardt et al., US Pat. No. 5,053,186). However, it would be beneficial to improve the specific activity of the .sup.186 Re formed via such conventional (n,.gamma.) approaches. Although the thermal and epithermal neutron cross-sections for Re-185 are high (106 b and 1632 b, respectively), the specific activity of .sup.186 6Re produced using conventional (n,.gamma.) methods in a reactor such as the Missouri University Research Reactor, MURR, with a thermal neutron flux 4.5.times.10.sup.14 n/cm.sup.2 s, is only about 3 Ci/mg Re. Since only a handful of reactors with higher neutron fluxes are operating in the world, using a higher neutron flux to enhance the specific activity of .sup.186 Re is not a viable commercial alternative.
Another approach for producing .sup.186 Re and .sup.188 Re via a (n,.gamma.) reaction involves the use of a Szilard-Chalmers reaction, in which the chemical and/or physical changes to a nuclide that result from a neutron-capture reaction are employed advantageously. The study of the chemical behavior of high energy atoms produced from nuclear reactions and/or radioactive decay processes, typically referred to as "hot atom" chemistry, was initiated in 1934 by L. Szilard and T. A. Chalmers, who demonstrated that after ethyl iodide was irradiated by thermal neutrons, some of the radioactive I-128 could be extracted from the ethyl iodide by water. (Szilard and Chalmers, Nature, 134, 462, 1934). According to most known Szilard-Chalmers techniques for producing .sup.186 Re and/or .sup.188 Re, an organic-Re complex is used as the starting material, and the .about.6 MeV of excitation gamma energy emitted by the rhenium nucleus after thermal neutron capture (ie., recoil energy) ruptures the organometallic bonds. Schubiger et al. (Technical University of Munich, Munich, Germany, 1995) reported irradiating a rhenium compound, Cp*ReO.sub.3 (pentamethyl cyclopentadienyl rheniumtrioxide), and observed that the activated compounds containing hot Re atoms decomposed to water soluble perrhenate while the rest of the molecules would remain in the organic phase. The specific activity of .sup.186 Re was, in this case, reported as being enhanced by a factor between 400-800 with neutron irradiation at 1.5.times.10.sup.13 n/cm .sup.2 s for 10 minutes. Zhang et al. reported a similar approach. (Zhang et al., Abstracts of Papers, Part I, 212th ACS National Meeting of the American Chemical Society, 1996). However, Szilard-Chalmers reactions normally do not result in significant specific activity enhancement in high neutron fluxes during longer periods of irradiation due to the increased radioactive (gamma and fast-neutron) decomposition of non-activated metal-organic bonds. In other words, experiments using organic compounds frequently produce large enhancement of specific activity for short irradiations in low neutron fluxes, but progressively fail to deliver enhanced specific activity product as irradiation time and neutron flux are increased.